Pierre-Olivier Gaudreau1, Marcelo V Negrao2, Kyle G Mitchell3, Alexandre Reuben2, Erin M Corsini3, Jun Li4, Tatiana V Karpinets4, Qi Wang5, Lixia Diao5, Jing Wang5, Lorenzo Federico6, Edwin R Parra-Cuentas7, Roohussaba Khairullah2, Carmen Behrens2, Arlene M Correa3, Daniel Gomez8, Latasha Little4, Curtis Gumbs4, Humam N Kadara7, Junya Fujimoto7, Daniel J McGrail9, Ara A Vaporciyan3, Stephen G Swisher3, Garrett Walsh3, Mara B Antonoff3, Annikka Weissferdt10, Hai Tran2, Emily Roarty2, Cara Haymaker7, Chantale Bernatchez11, Jianhua Zhang4, P Andrew Futreal4, Ignacio I Wistuba7, Tina Cascone2, John V Heymach2, Boris Sepesi3, Jianjun Zhang12, Don L Gibbons13. 1. Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Ontario, Canada. 2. Department of Thoracic and Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. 9. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 10. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 11. Biologics Development Department, The University of Texas MD Anderson Cancer Center, Houston, Texas. 12. Department of Thoracic and Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: jzhang20@mdanderson.org. 13. Department of Oncology, Queens' University and the Canadian Cancer Trials Group, Kingston, Ontario, Canada; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract
INTRODUCTION: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. METHODS: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). RESULTS: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3- tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. CONCLUSIONS: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
INTRODUCTION: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. METHODS: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). RESULTS: NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3- tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. CONCLUSIONS: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.
Authors: Leena Gandhi; Delvys Rodríguez-Abreu; Shirish Gadgeel; Emilio Esteban; Enriqueta Felip; Flávia De Angelis; Manuel Domine; Philip Clingan; Maximilian J Hochmair; Steven F Powell; Susanna Y-S Cheng; Helge G Bischoff; Nir Peled; Francesco Grossi; Ross R Jennens; Martin Reck; Rina Hui; Edward B Garon; Michael Boyer; Belén Rubio-Viqueira; Silvia Novello; Takayasu Kurata; Jhanelle E Gray; John Vida; Ziwen Wei; Jing Yang; Harry Raftopoulos; M Catherine Pietanza; Marina C Garassino Journal: N Engl J Med Date: 2018-04-16 Impact factor: 91.245
Authors: Nasser Hanna; David Johnson; Sarah Temin; Sherman Baker; Julie Brahmer; Peter M Ellis; Giuseppe Giaccone; Paul J Hesketh; Ishmael Jaiyesimi; Natasha B Leighl; Gregory J Riely; Joan H Schiller; Bryan J Schneider; Thomas J Smith; Joan Tashbar; William A Biermann; Gregory Masters Journal: J Clin Oncol Date: 2017-08-14 Impact factor: 44.544
Authors: Achim Rittmeyer; Fabrice Barlesi; Daniel Waterkamp; Keunchil Park; Fortunato Ciardiello; Joachim von Pawel; Shirish M Gadgeel; Toyoaki Hida; Dariusz M Kowalski; Manuel Cobo Dols; Diego L Cortinovis; Joseph Leach; Jonathan Polikoff; Carlos Barrios; Fairooz Kabbinavar; Osvaldo Arén Frontera; Filippo De Marinis; Hande Turna; Jong-Seok Lee; Marcus Ballinger; Marcin Kowanetz; Pei He; Daniel S Chen; Alan Sandler; David R Gandara Journal: Lancet Date: 2016-12-13 Impact factor: 79.321
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: Jernej Godec; Yan Tan; Arthur Liberzon; Pablo Tamayo; Sanchita Bhattacharya; Atul J Butte; Jill P Mesirov; W Nicholas Haining Journal: Immunity Date: 2016-01-12 Impact factor: 31.745
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245
Authors: Jean-Pierre Pignon; Hélène Tribodet; Giorgio V Scagliotti; Jean-Yves Douillard; Frances A Shepherd; Richard J Stephens; Ariane Dunant; Valter Torri; Rafael Rosell; Lesley Seymour; Stephen G Spiro; Estelle Rolland; Roldano Fossati; Delphine Aubert; Keyue Ding; David Waller; Thierry Le Chevalier Journal: J Clin Oncol Date: 2008-05-27 Impact factor: 44.544
Authors: Kathryn E Cole; Quan P Ly; Michael A Hollingsworth; Jesse L Cox; Kurt W Fisher; James C Padussis; Jason M Foster; Luciano M Vargas; James E Talmadge Journal: Int Immunopharmacol Date: 2022-02-21 Impact factor: 4.932
Authors: Stephanie T Schmidt; Neal Akhave; Ryan E Knightly; Alexandre Reuben; Natalie Vokes; Jianhua Zhang; Jun Li; Junya Fujimoto; Lauren A Byers; Beatriz Sanchez-Espiridion; Lixia Diao; Jing Wang; Lorenzo Federico; Marie-Andree Forget; Daniel J McGrail; Annikka Weissferdt; Shiaw-Yih Lin; Younghee Lee; Erika Suzuki; Jeffrey J Kovacs; Carmen Behrens; Ignacio I Wistuba; Andrew Futreal; Ara Vaporciyan; Boris Sepesi; John V Heymach; Chantale Bernatchez; Cara Haymaker; Tina Cascone; Jianjun Zhang; Christopher A Bristow; Timothy P Heffernan; Marcelo V Negrao; Don L Gibbons Journal: JCO Clin Cancer Inform Date: 2022-07
Authors: Raquel Laza-Briviesca; Alberto Cruz-Bermúdez; Ernest Nadal; Amelia Insa; María Del Rosario García-Campelo; Gerardo Huidobro; Manuel Dómine; Margarita Majem; Delvys Rodríguez-Abreu; Alex Martínez-Martí; Javier De Castro Carpeño; Manuel Cobo; Guillermo López Vivanco; Edel Del Barco; Reyes Bernabé Caro; Nuria Viñolas; Isidoro Barneto Aranda; Santiago Viteri; Bartomeu Massuti; Marta Casarrubios; Belén Sierra-Rodero; Carlos Tarín; Aránzazu García-Grande; Cara Haymaker; Ignacio I Wistuba; Atocha Romero; Fernando Franco; Mariano Provencio Journal: Clin Transl Med Date: 2021-07